Polymer particles

ABSTRACT

Biodegradable, cross-linked polymer particle embolics and methods of making the same are described. The particle embolics can be used as embolization agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/369,213, filed Dec. 5, 2016, which is a continuation of U.S. patentapplication Ser. No. 14/491,776, filed Sep. 19, 2014 (now U.S. Pat. No.9,546,236), which claims the benefit of U.S. provisional patentapplication No. 61/880,036, filed Sep. 19, 2013, the entire disclosureeach of which is incorporated herein by reference.

FIELD

Biodegradable polymer particles for the occlusion of vascular sites andcavities within the body, such as the embolization of hypervascularizedtumors or arteriovenous malformations are described.

SUMMARY

Described herein generally are biodegradable, cross-linked polymerparticles. In some embodiments, the particles can have a spherical shapeor be substantially spherical. Thus, the particles described herein canbe referred to as microshperes or polymer spheres. These polymers can beused for/in embolization. The polymer particles can include and/or beformed of one or more monomers and a crosslinker susceptible to chemicalhydrolysis or enzymatic action.

The biodegradable polymer particles described herein can be utilized forthe occlusion of vascular sites, bodily lumen, and other cavities withinthe body. In some embodiments, the polymer particles can be used forsuch purposes as the embolization of hypervascularized tumors orarteriovenous malformations.

Polymer particles can comprise: at least one monomer and at least onecrosslinker. In some embodiments, the polymer particles can besusceptible to degradation through chemical hydrolysis or enzymaticaction. Particles as described herein can have various sizes dependingon a particular use, but generally can have diameters between about 40μm and about 1,200 μm or between about 75 μm and about 1,200 μm.

Methods of making a polymer particle as described herein are alsodescribed. These methods comprise: preparing an aqueous prepolymersolution including at least one monomer, at least one crosslinkersusceptible to degradation through chemical hydrolysis or enzymaticaction, and an initiator; dispersing the aqueous prepolymer solution inmineral oil; and forming the polymer particles via polymerization of themonomers.

Other methods to form polymer particles can include: reacting aprepolymer solution in an oil to form the polymer particles. Theprepolymer solution can include at least one monomer comprising at leastone functional group, at least one crosslinker susceptible todegradation through chemical hydrolysis or enzymatic action, and aninitiator.

The crosslinkers used to form the polymer particles can impartbiodegradability to the particles. For example, the crosslinker caninclude at least one linkage susceptible to degradation through chemicalhydrolysis or enzymatic action. The cross-linker can be glycidyl,glycidyl amino, thioester, or protein based. A glycidyl basedcrosslinker may be bis-glycidyl amino alcohol. A protein basedcrosslinker may be bi-functionalizedmethacryloyl-Ala-Pro-Gly-Leu-AEE-methacrylate.

DRAWINGS

FIG. 1 is a graph showing the stages of degradation for differentpolymer particles.

FIG. 2 is a graph showing time to full degradation for different polymerparticles.

FIG. 3 is another graph showing scoring for polymer particledegradation.

DETAILED DESCRIPTION

Described herein generally are particles made of polymer material. Thepolymer material can be a reaction product of one or more monomers and acrosslinker. In some embodiments, the polymer particles can besusceptible to hydrolysis or enzymatic action. The particles can bereferred to herein as being microparticles, microspheres and the like.The particles can have a diameter of between about 40 μm and about 1,200μm or between about 75 μm and about 1,200 μm. The particles can also becompressible and/or durable for ease of delivery through a medicaldevice such as a needle or catheter. The particles can also bebiodegradable once delivered.

The particles can be formed from a mixture such as a prepolymersolution. The prepolymer solution can comprise: (i) one or more monomersthat contain a singular functional group amenable to polymerization and(ii) one or more crosslinkers. In some embodiments, a polymerizationinitiator may be utilized.

In some embodiments, if one of the monomer(s) and/or crosslinker(s) is asolid, a solvent can be utilized in the preparation of the particles foruse as embolics. If liquid monomers and crosslinkers are utilized, asolvent may not be required. In some embodiments, even when using liquidmonomers and crosslinkers, a solvent may still be used. Solvents mayinclude any liquid that can dissolve or substantially dissolve amonomer, monomer mixture, and/or a crosslinker. Any aqueous or organicsolvent may be used that dissolves the desired monomer(s),crosslinker(s), and/or polymerization initiators. If an organic solventis used, an aqueous media may be required for dispersion. In oneembodiment, the solvent can be water. Additionally, solutes, e.g. sodiumchloride, may be added to the solvent to increase the rate ofpolymerization. Solvent concentrations can be about 10% w/w, about 20%w/w, about 30% w/w, about 40% w/w, about 50% w/w, about 60% w/w, about70% w/w, about 80% w/w, about 90% w/w, between about 20% w/w and about80% w/w, between about 50% w/w and about 80% w/w, or between about 30%w/w and about 60% w/w of the solution.

Any type of crosslinking chemistry can be utilized to prepare thedescribed polymer particles. In some embodiments, for examplecrosslinking chemistries such as, but not limited tonucleophile/N-hydroxysuccinimide esters, nucleophile/halide, vinylsulfone/acrylate or maleimide/acrylate can be used. In one exampleembodiment, free radical polymerization can be used. As such, monomerswith a singular ethylenically unsaturated group, such as acrylate,acrylamide, methacrylate, methacrylamide, and vinyl, may be used whenemploying free radical polymerization.

Any amount of monomer can be used that allows for a desired particle.Monomer concentration in the solvent can be about 1% w/w, about 2% w/w,about 3% w/w, about 4% w/w, about 5% w/w, about 10% w/w, about 15% w/w,about 20% w/w, about 30% w/w, about 40% w/w, about 50% w/w, about 60%w/w, about 70% w/w, about 80% w/w, about 90% w/w, about 100% w/w,between about 1% w/w and about 100% w/w, between about 40% w/w and about60% w/w, between about 50% w/w and about 60% w/w, or between about 40%w/w and about 60% w/w.

Monomers can be selected based on imparting desired chemical and/ormechanical properties to the polymer particle or particle embolic. Ifdesired, uncharged, reactive moieties can be introduced into theparticle embolic. For example, hydroxyl groups can be introduced intothe particle embolic with the addition of 2-hydroxyethyl acrylate,2-hydroxymethacrylate, derivatives thereof, or combinations thereof.Alternatively, uncharged, relatively unreactive moieties can beintroduced into the particle embolic. For example, acrylamide,methacrylamide, methyl methacrylate, derivatives thereof, orcombinations thereof can be added.

In one embodiment, polymer particles can be prepared from monomershaving a single functional group suitable for polymerization. Functionalgroups can include those suitable to free radical polymerization, suchas acrylate, acrylamide, methacrylate, and methacrylamide. Otherpolymerization schemes can include, but are not limited tonucleophile/N-hydroxysuccinimide esters, nucleophile/halide, vinylsulfone/acrylate or maleimide/acrylate. Selection of the monomers isgoverned by the desired mechanical properties of the resulting particleand minimizing the biological effects of degradation products.

In some embodiments, the monomer can additionally contain an ionizablefunctional group that is basic (e.g. amines, derivatives thereof, orcombinations thereof). The amine group may be protonated at pH's lessthan the pKa of the amine, and deprotonated at pH's greater than the pKaof the amine. In other embodiments, the monomer additionally contains anionizable functional group that is acidic (e.g. carboxylic acids,sulfonic acids, derivatives thereof, or combinations thereof). The acidgroup may be deprotonated at pHs greater than the pKa of the acid, andprotonated at pHs less than the pKa of the acid.

If the binding of positively charged drugs is desired, monomers withnegatively charged moieties, e.g. carboxylic acids, or other acidicmoieties can be polymerized into the particle embolic. Acidic,ionizable, ethylenically unsaturated monomers can include, but are notlimited to, acrylic acid, methacrylic acid, 3-sulfopropyl acrylate,3-sulfopropyl methacrylate, derivatives thereof, combinations thereof,and salts thereof. On the other hand, if the binding of negativelycharged drugs is desired, monomers with positively charged moieties,e.g. amines, or other basic moieties can be included. Basic, ionizable,ethylenically unsaturated monomers can include, but are not limited toamino ethyl methacrylate, aminopropyl methacrylate, derivatives thereof,combinations thereof, and salts thereof.

An additional factor in monomer selection can be the desire fordegradation products of the particle embolic to elicit a negligibleresponse from the host. In other embodiments, there can be desire fordegradation products of the particles to elicit substantially noresponse from the host

A crosslinker can include one or more polymerizable groups, can joinmonomer chains together, and permit the formation of solid particles.Biodegradation can be imparted to the particle embolic by utilizing acrosslinker with linkages susceptible to degradation in a physiologicalenvironment. Over time in vivo, linkages can break and the polymerchains may no longer be bound together. The judicious selection ofmonomers permits the formation of water-soluble degradation productsthat diffuse away and are cleared by the host. Linkages susceptible tohydrolysis, such as esters, thioesters, carbamates, and carbonates, orpeptides degraded by enzymes can be used in biodegradable products.

In one embodiment, one or more crosslinkers can contain at least twofunctional groups suitable for polymerization and at least one linkagesusceptible to breakage to impart biodegradation to the polymerparticle. Linkages susceptible to breakage in a physiologicalenvironment can include, but are not limited to those susceptible tohydrolysis, including esters, thioesters, carbamates, and carbonates,and those susceptible to enzymatic action, including peptides that arecleaved by matrix metalloproteinases, collagenases, elastases, andcathepsins. In some embodiments, multiple crosslinkers can be utilizedto control degradation rate in a manner not possible with only onecrosslinker. In one embodiment, at least one crosslinker is susceptibleto hydrolysis and at least one crosslinker is susceptible to enzymaticdegradation.

In some embodiments, the at least one linkage is a peptide cleavable bymatrix metalloproteinases, a peptide cleavable by matrix collagenases, apeptide cleavable by matrix elastases, a peptide cleavable by matrixcathepsins, or a combination thereof.

In other embodiments, the polymers can include a second crosslinkerincluding a second linkage selected from an ester, a thioester, acarbonate, a carbamate, a peptide cleavable by matrixmetalloproteinases, a peptide cleavable by matrix collagenases, apeptide cleavable by matrix elastases, and a peptide cleavable by matrixcathepsins.

In still other embodiments, the polymers can include a third, fourth,fifth or more crosslinkers each including the same or a differentlinkage.

Crosslinkers can include peptide based crosslinkers, carbonate basedcrosslinkers, bis glycidyl amine crosslinkers, TMP gly estercrosslinkers, di thio ester crosslinkers, or jeffamine glycidyl aminecrosslinkers. Preferred concentrations of the crosslinkers in the finalproduct can be about 0.05% w/w, about 0.1% w/w, about 0.5% w/w, about1.0% w/w, about 2.0% w/w, about 3.0% w/w, about 4.0% w/w, between about0.1% w/w and about 4.0% w/w, between about 0.5% w/w and about 2% w/w, orbetween about 1% w/w and about 1.5% w/w. A skilled artisan understandshow to calculate final concentrations based on the amount in solventalready discussed.

In one embodiment, crosslinkers can be peptide based compounds. In oneembodiment, a peptide based crosslinker can be

or a derivative thereof.

In another embodiment, the peptide based crosslinker can be

or a derivative thereof.

In another embodiment, the peptide based crosslinker can bebi-functionalized methacryloyl-Ala-Pro-Gly-Leu-AEE-methacrylate.

In another embodiment, crosslinkers can have a structure

wherein n is 1 to 20;m is 1 to 20; andX is O or S.

In another embodiment, the crosslinker can have a structure

wherein n is 1 to 20;m is 1 to 20.

In another embodiment, the crosslinker can have a structure

A crosslinker can also have a structure

wherein o is 1 to 20; andp is 1 to 20.

In one embodiment, the structure can be

A crosslinker can further have a structure

wherein q is 1 to 10. In one embodiment, q is 1.

A crosslinker can further have a structure

wherein r is 1 to 20; andY and Z are each independently selected from O, S, and NH.

In one embodiment, the crosslinker can have a structure

wherein r is 1 to 20.

Further, in another embodiment, the crosslinker can have a structure

wherein G, H and J are each independently CH₂, O, S, NH, or not present,a, b, and c are each independently 1 to 20; andg is 1 to 20.

In another embodiment, a, b, and c are each independently 1 to 10. Instill another embodiment, G, H and J are each independently O or NH.

In one embodiment, the crosslinker has a structure

wherein a, b, and c are each independently 1 to 20.Further, in another embodiment, the crosslinker can have a structure

wherein L, M and N are each independently CH₂, O, S, NH, or not present,d, e, and f are each independently 1 to 20; andh is 1 to 20.

In another embodiment, d, e, and f are each independently 1 to 10. Instill another embodiment, L, M and N are each independently O or NH.

In one embodiment, the crosslinker has a structure

wherein d, e, and f are each independently 1 to 20.

A crosslinker can also have a structure

wherein s is 1 to 20;wherein t is 1 to 20; andX¹, X², X³ and X⁴ are each independently O or S.

In one embodiment, the structure can be

A crosslinker can also have a structure

In some embodiments, a crosslinker can be a tetra ester, a tetrathioester or a dithio ester. In other embodiments, the crosslinker canbe a peptide crosslinker or a carbonate crosslinker. A glycidyl basedcrosslinker may be bis-glycidyl amino alcohol.

Polymerization of the prepolymer solution can be by reduction-oxidation,radiation, heat, or any other method known in the art. Radiationcross-linking of the prepolymer solution can be achieved withultraviolet light or visible light with suitable initiators or ionizingradiation (e.g. electron beam or gamma ray) without initiators.Cross-linking can be achieved by application of heat, either byconventionally heating the solution using a heat source such as aheating well, or by application of infrared light to the monomersolution. The free radical polymerization of the monomer(s) andcrosslinker(s) is preferred and requires an initiator to start thereaction. In a preferred embodiment, the cross-linking method utilizesazobisisobutyronitrile (AIBN) or another water soluble AIBN derivativesuch as (2,2′-azobis(2-methylpropionamidine)dihydrochloride). Othercross-linking agents can include, but are not limited toN,N,N′,N′-tetramethylethylenediamine, ammonium persulfate, benzoylperoxides, and combinations thereof, including azobisisobutyronitriles.A preferred initiator can be a combination ofN,N,N′,N′-tetramethylethylenediamine and ammonium persulfate.

Polymer particles can be produced or formed by methods including:reacting a prepolymer solution including at least one monomer includingat least one functional group, at least one crosslinker susceptible todegradation through chemical hydrolysis or enzymatic action, and aninitiator in an oil.

The prepolymer solution can be prepared by dissolving the monomer(s),crosslinker(s), and optionally initiator(s) in the solvent. The particleembolics can be prepared by emulsion polymerization. A non-solvent forthe monomer solution, typically mineral oil when the monomer solvent iswater, is sonicated to remove any entrapped oxygen. The mineral oil anda surfactant are added to the reaction vessel. An overhead stirrer isplaced in the reaction vessel. The reaction vessel is then sealed,degassed under vacuum, and sparged with an inert gas such as argon. Theinitiator component N,N,N′,N′-tetramethylethylenediamine is added to thereaction vessel and stirring commenced. Ammonium persulfate is added tothe polymerization solution and both are then added to the reactionvessel, where the stirring suspends droplets of the prepolymer solutionin the mineral oil.

The rate of stirring can affect particle size, with faster stirringproducing smaller particles. Stirring rates can be about 100 rpm, about200 rpm, about 300 rpm, about 400 rpm, about 500 rpm, about 600 rpm,about 700 rpm, about 800 rpm, about 900 rpm, about 1,000 rpm, about1,100 rpm, about 1,200 rpm, about 1,300 rpm, between about 200 rpm andabout 1,200 rpm, between about 400 rpm and about 1,000 rpm, at leastabout 100 rpm, at least about 200 rpm, at most about 1,300 rpm, or atmost about 1,200 rpm to produce particles with desired diameters.

The polymer particles described herein can have a generally orsubstantially spherical shape. The substantially spherical or sphericalparticles can have diameters of about 10 μm, about 20 μm, about 30 μm,about 40 μm, about 50 μm, about 60 μm, about 75 μm, about 100 μm, about200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about700 μm, about 800 μm, about 900 μm, about 1,000 μm, about 1,100 μm,about 1,200 μm, about 1,300 μm, about 1,400 μm, about 1,500 μm, about1,600 μm, between about 50 μm and about 1,500 μm, between about 100 μmand about 1,000 μm, between about 75 μm and about 1,200 μm, at leastabout 50 μm, at least about 80 μm, at most about 1,500 μm, or at mostabout 1,200 μm. In some embodiments, the diameter can be between about40 μm and about 1,200 μm, between about 40 μm and about 60 μm, orbetween about 75 μm and about 1,200 μm.

The polymer particles can retain their diameters even after injectionthrough a catheter or other delivery device. In other words, the polymerparticles may not fall apart or otherwise fracture during delivery. Insome embodiments, the polymer particles can retain about 99%, about 98%,about 97%, about 96%, about 95%, about 90%, greater than about 99%,greater than about 98%, greater than about 97%, greater than about 96%,greater than about 95%, greater than about 90%, between about 90% andabout 100% of their diameter after delivery.

The polymer particles can also have a characteristic circularity or havea relative shape that is substantially circular. This characteristicdescribes or defines the form of a region on the basis of itscircularity. Polymer particles as described herein can have a fractionof circularity of about 0.8, 0.9, 0.95, 0.96, 0.97, 0.98, 0.99, greaterthan about 0.8, greater than about 0.9, or greater than about 0.95. Inone embodiment, the circularity of the polymer particles is greater thanabout 0.9.

The polymer particles can retain their circularity even after injectionthrough a catheter or other delivery device. In some embodiments, thepolymer particles can retain about 99%, about 98%, about 97%, about 96%,about 95%, about 90%, greater than about 99%, greater than about 98%,greater than about 97%, greater than about 96%, greater than about 95%,greater than about 90%, between about 90% and about 100% of theircircularity after delivery.

Polymerization can be allowed to proceed as long as necessary to produceparticles with desired resiliency. Polymerization can be allowed toproceed for about 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 6 hr, 7 hr, 8 hr, 9 hr,10 hr, 11 hr, 12 hr, 18 hr, 24 hr, 48 hr, 72 hr, 96 hr, between about 1hr and about 12 hr, between about 1 hr and about 6 hr, between about 4hr and about 12 hr, between about 6 hr and about 24 hr, between about 1hr and about 96 hr, between about 12 hr and about 72 hr, or at leastabout 6 hours.

Polymerization can be run at a temperature to produce particles withdesired resiliency and/or reaction time. Polymerization can be run at atemperature of about 10° C., about 20° C., about 30° C., about 40° C.,about 50° C., about 60° C., about 70° C., about 80° C., about 90° C.,about 100° C., between about 10° C. and about 100° C., between about 10°C. and about 30° C., at least about 20° C., at most about 100° C., or atabout room temperature. In one embodiment, polymerization occurs at roomtemperature.

After the polymerization is complete, the polymer particles are washedto remove any solute, mineral oil, unreacted monomer(s), and/or unboundoligomers. Any solvent may be utilized, but care should be taken ifaqueous solutions are used to wash particles with linkages susceptibleto hydrolysis. Preferred washing solutions can include, but are notlimited to acetone, alcohols, water and a surfactant, water, saline,buffered saline, and saline and a surfactant.

Optionally, the washed polymer particles can then be dyed to permitvisualization before injection into a microcatheter. A dye bath can bemade by dissolving sodium carbonate and the desired dye in water.Particle embolics are added to the dye bath and stirred. After the dyingprocess, any unbound dye is removed through washing. After dying andwashing, the particles can be packaged into vials or syringes, andsterilized.

After the preparation of the particle embolics, they can be optionallydyed to permit visualization during preparation by the physician. Any ofthe dyes from the family of reactive dyes which bond covalently to theparticle embolics can be used. Dyes can include, but are not limited to,reactive blue 21, reactive orange 78, reactive yellow 15, reactive blueNo. 19, reactive blue No. 4, C.I. reactive red 11, C.I. reactive yellow86, C.I. reactive blue 163, C.I. reactive red 180, C.I. reactive black5, C.I. reactive orange 78, C.I. reactive yellow 15, C.I. reactive blueNo. 19, C.I. reactive blue 21, or any of the color additives. Some coloradditives are approved for use by the FDA part 73, subpart D. In otherembodiments, a dye that can irreversibly bond to the polymer matrix ofthe particle embolic may be used.

If the herein described polymer particle or microsphere does notadequately bind any of the reactive dyes described above, a monomercontaining an amine can be added to the monomer solution in an amount toachieve the desired coloration. Even if the polymer particle ormicrosphere does adequately bind the reactive dyes described above, amonomer containing an amine can be added to the monomer solution.Examples of suitable amine containing monomers include aminopropylmethacrylate, aminoethyl methacrylate, aminopropyl acrylate, aminoethylacrylate, derivatives thereof, combinations thereof, and salts thereof.Preferred concentrations of the amine containing monomers in the finalproduct can be less than or equal to about 1% w/w.

The particles described herein can be sterilized without substantiallydegrading the polymer. After sterilization, at least about 50%, about60%, about 70%, about 80%, about 90%, about 95% about 99% or about 100%of the polymer can remain intact. In one embodiment, the sterilizationmethod can be autoclaving and can be utilized before administration.

The final polymer particle preparation can be delivered to the site tobe embolized via a catheter, microcatheter, needle, or other similardelivery device. A radiopaque contrast agent can be thoroughly mixedwith the particle preparation in a syringe and injected through acatheter until blood flow is determined to be occluded from the site byinterventional imaging techniques.

In some embodiments, it may be desirable for the particles to degradeover time. In other words, the particles can be degradable and/orbiodegradable. In such embodiments, the particles can degrade to lessthan about 40%, about 30% about 20%, about 10%, about 5% or about 1%intact after about 2 days, 3 days, 5 days, about 2 weeks, about 1 month,about 2 months, about 6 months, about 9 months, about a year, about 2years, about 5 years, or about 10 years. In one embodiment, theparticles can be substantially degraded in less than about 1 month. Inanother embodiment, the particles can be substantially degraded in lessthan about 6 months.

In some embodiments, degradability can be accelerated with anappropriate and/or adequate enzyme. In some embodiments, the polymerparticles can be injected along with an enzyme that can accelerate thedegradation of the particles. In other embodiments, an enzyme can bedelivered to the site of the implanted particles at a remote time andaccelerate degradation at that time.

In some embodiments, the greater the percentage of a crosslinker in thefinal polymer particles, the longer degradation takes. Additionally, thelarger the particle diameter, the longer the degradation. Thus, theparticles with the longest degradation time are those that have thelargest concentration of crosslinker and the largest diameter. These twoproperties can be varied to tailor degradation time as needed.

The polymer particles described herein can be compressible yet durableenough not to break apart or fragment. Substantially no change incircularity or diameter of particles occurs during delivery through amicrocatheter. In other words, after delivery through a microcatheter,the polymer particles described herein remain greater than about 60%,about 70% about 80%, about 90%, about 95%, about 99% or about 100%intact after delivery.

Further, in some embodiments, the particles can stick to the tissueand/or remain in place through friction with the tissues. In otherembodiments, the particles can act as a plug in a vessel held in placeby the flow and pressure of the blood itself. In still otherembodiments, the particles can be cohesive enough to stick to oneanother to aid in agglomerating particles at a particular site ofaction.

Polymer particles described can be delivered through a microcatheter orother appropriate delivery device to a remote tissue or can be injectedthrough a needle to local tissues. The polymer particles can be used forocclusion of vascular sites and cavities within the body.

In some embodiments, the polymer particles can be configured forembolization of hypervascularized tumors or arteriovenous malformations.In some embodiments, a patient can be selected that exhibits ahypervascularized tumor and/or an arteriovenous malformation. Amicrocatheter can be navigated to the location of the tumor ormalformation. Polymer particles as described herein can be injected intothat site to stabilize it thereby treating the patient's condition.

Example 1 Preparation of a Glycidyl-Based Crosslinker

A 10 g (67.6 mmol) aliquot of 2,2′-(ethylenedioxy)bis(ethylamine) wasmixed with 10 g (70.4 mmol) of glycidyl methacrylate, and 3 g of silicagel (Aldrich 645524, 60 Angstrom, 200-425 mesh). After stirring for 1hr, another 9 g (63.4 mmol) of glycidyl methacrylate was added and thesuspension was stirred for an additional 1.5 hr. The mixture was dilutedwith 200 mL chloroform and filtered through a 600 mL fritted glassBuchner funnel to remove the silica gel. LC-MS analysis of the resultantchloroform solution showed no mono glycidyl amino alcohol and mainlybis-glycidyl amino alcohol at [M+H]+ m/z 433.2. The solution wasconcentrated to about 50 g in vacuo. The resultant heavy syrup wasdiluted to 100 mL with acetonitrile and stored at −80° C.

Example 2 Preparation of a Peptide-Based Crosslinker

A heterobifunctional, tetrapeptide(Acryloyl-Ala-Pro-Gly-Leu-AEE-N-hydroxysuccinimide) was provided(Bachem, Torrance, Calif.). The peptide (653 mg, 1 mmol) was dissolvedin 5 mL DMF and N-(3-aminopropyl)methacrylamide hydrochloride (190 mg,1.1 mmol) and N,N-diispropylethylamine (174 μL, 1 mmol) were added.After 2 hr, 20 mg of butylated hydroxytoluene was added and the reactionmixture was exposed to air. The reaction mixture was precipitated with200 mL of ethyl ether. The solids were collected using centrifugation.The pellet was re-dissolved in a 90/5/5 solution ofchloroform/methanol/methanol+5% aqueous ammonia and applied to 50 g ofsilica gel in a 5×20 cm column (Aldrich, 60 Angstrom, 200-425 mesh). Thesilica gel column was developed with 500 mL of 90/5/5 solution ofchloroform/methanol/methanol+5% aqueous ammonia and the peptidecontaining eluent was concentrated in vacuo to yield 110 mg of paleyellow oil. The pale yellow oil was dissolved in 10 mL methanol andstored at −80° C. LC-MS analysis of the product showed the desired[M+H]⁺ at m/z 680 and [M+Na]⁺ at m/z 702.

Example 3 MA-AEEAc-ALAL-AEEAc-MA, ALAL Tetrapeptide Crosslinker

To 841 mg (1 mmol) of NHS ester, MA-AEEAc-ALAL-AEEAc-NHS was added 179mg of 3-aminopropyl methacrylate-HCl into a clean dry 15 mL flask with adry stir bar and a dry septum, followed by 5 mL of dry dimethylformamide. Upon stirring, a clear solution resulted and 200 μL (1 mmol)of diisopropylethylamine was added all at once. After one hour, thereaction mixture was transferred to a 250 mL pear shaped flask using 3×5mL of methanol and placed on the vacuum (vac) line overnight. The nextday the reaction mixture was transferred to a scintillation vial with 2mL of methanol, to give approx. 35% solids, and stored at −80° C. Thecrude crosslinker above gives a single HPLC peak gives [M+H]⁺ at m/z of869.9, molecular mass calculated for C₄₁H₇₂N₈O₁₂ is 868.5.

Example 4 Carbonate Crosslinkers

To 33 g (100 mmol) of cesium carbonate suspended in 500 mL of 1:1acetonitrile:methanol was added 17.2 g (200 mmol) of methacrylic acidover one hour with good stirring. After stirring an additional 2 hr,solvent was removed from the reaction mixture and the residue wassuspended in 500 mL of dry ether and collected by filtration onto a dry600 mL Buchner funnel with a medium frit. After carefully rinsing thesolids on the funnel with dry ether several times, the solids were driedin the vacuum oven overnight to give 45 g of a hygroscopic beige powder(Compound A) which has to quickly be placed into a dry environment.

HEMA-1-Chloroethyl carbonate: To 24 mL of HEMA (200 mmol) in 1000 mL ofdry ether was added 16.8 mL (213 mmol) of pyridine at 4-10° C., underargon. To this solution was added 21.3 mL (200 mmol) of 1-chloroethylchlorocarbonate, drop wise with stirring over 0.5 hour. After stirring0.5 hr at 4-10° C., the heavy precipitate (Compound B) was removed byfiltration and the filtrate was concentrated to an oil in vacuo,yielding 44 g (100%).

To 4.4 g (20 mmol) of Compound B in 40 mL of anhydrous dimethylformamide, was added 0.9 g (4.0 mmol) of Compound A at 100° C., underargon, with good stirring. After 15 min, another 1.2 g (5.4 mmol) ofCompound A was added at 100° C., under argon, with good stirringfollowed by a final 0.9 g (4.0 mmol), under the same conditions, for atotal of 2.9 g Compound A (13.4 mmol). The yellow brown reaction mixturewas heated at 100° C. for an additional 3 hr and after cooling to roomtemperature the solvent was removed in vacuo, and the residue was lefton the vacuum line overnight. The residue was taken up in 50 mL of 1:1chloroform:hexane, applied to a 750 gram gold column, and eluted withhexane and then 0-20% ethyl acetate in hexane. The following carbonate

came out starting at 27 min and the following carbonate

came off at 32 min.

Example 5 TMP Gly Ester

TMP-Chloroacetamide: To 13.2 g of triamino trimethylol propaneethoxylate in 250 mL of dry tetrahydrofuran (THF) was added 6.32 g (80mmol) of pyridine and this solution was added to 6.44 g of chloroacetylchloride in 250 mL of THF with good stirring, at 4-10° C. under argon(Ar). After stirring for 15 min, the reaction mixture was warmed to roomtemperature and the THF and other volatile material were removed invacuo. The resulting solids were dissolved into 200 mL of chloroformwhich was in turn washed with 100 mL of saturated aqueous sodiumbicarbonate, dried over magnesium sulfate and the solvent was removed invacuo.

TMP-NH-Gly-Methacrylate: To approx 15 g of material above dissolved in75 mL of anhydrous dimethyl formamide was added 18 g of cesiummethacrylate and the resulting suspension heated at 40-50° C. for 2 hrs.

After precipitation with 500 mL of chloroform, the inorganic salts werecollected by filtration and the filtrate was concentrated to an oil invacuo to give 18 g of a reddish brown oil. This oil could be polymerizedwith AIBN at 80° C., in IPA to a hard pellet. Chromatography on 6 g ofthis through a plug of the above silica with 1200 mL of 2-20% methanolin chloroform, gave 6 g of light red colored material.

Example 6 Dithio Ester

To 6.6 mL (40 mmol) of 2,2′-(ethylenedioxy)ethanedithiol in 200 mL oftetrahydrofuran (THF) was added 20.9 mL of diisopropylethyl amine andthe resulting dry solution was added to 11.5 mL of methacryloyl chloride(120 mmol) in 200 mL of dry THF, at −5° C., with good stirring over 1hr. The reaction mixture was stirred at 0° C. for 1 hr and at 20° C. for1 hr at which point 10 mL of isopropyl alcohol was added and the solventwas removed in vacuo.

The residue was applied to a 330 g silica (gold) column in a minimumvolume of chloroform and the column was eluted with 0-5% isopropylalcohol in methylene chloride at 200 mL/min. The fraction which elutedat 13-14 minutes as a single peak was isolated as 1.3 g of yellow oil.AIBN initiated reaction of 50 mg of this material displayed a hardpellet.

Example 7 Dithio Ester

To 40 mL of dry tetrahydrofuran (THF), at 0° C., containing 0.4 mL (4mmol) of methacryloyl chloride was added 20 mL of dry THF containing 2.0g (1.33 mmol) of poly(ethylene glycol) dithiol 1500 mw and 0.7 mL (4.0mmol) diisopropylethylamine, dropwise over 5 min, with rapid stirring.After stirring for 2 hrs, the reaction mixture was warmed to roomtemperature and solvent was removed in vacuo. Then, 100 mL of chloroformwas used to dissolve reaction mixture and this was removed in vacuo, toentrain methacryloyl chloride.

The reaction mixture was placed on the vacuum line overnight atapproximately 30 microns and a yellow solid formed. AIBN initiatedreaction of 50 mg of this in 50 microliters of isopropyl alcoholresulted in a sponge of yellow gel.

Example 8 Jeffamine Glycidyl Amine

To 11 g of Jeffamine (25 mmol) is added 10.5 g of glycidyl methacrylate(75 mmol) followed by 4 g of silica gel and 100 mg of butylatedhydroxytoluene. The reaction mixture was stirred at 20° C. After 2 hrs,50 mL of chloroform was added to the thickening reaction mixture andstirring was continued. After another 18 hrs, an additional 200 mL ofchloroform was added and the reaction mixture was filtered to removesilica gel and most of the solvent removed in vacuo. The residue wasdissolved in 20 mL of isopropyl alcohol to give 40 mL of approximately50% of Jeffamine glycidyl amine.

Example 9 Particle Prepared with a Glycidyl-Based Crosslinker

A prepolymer solution was prepared by dissolving 6.2 g of acrylamide,14.6 g of 3-sulfopropyl acrylate potassium salt, and 0.3 g of aglycidyl-based crosslinker, prepared as in Example 1, in 20.0 g ofdistilled water. This solution was filtered and then vacuum degassed for5 min and flushed with argon. A liter of mineral oil was sonicated for 1hr and then added to a sealed reaction vessel equipped with an overheadstirring element. The vessel was vacuum degassed for at least 1 hr andthen the vacuum replaced with argon.N,N,N′,N′-tetramethylethylenediamine, approximately 3 mL, was added tothe reaction vessel and overhead stirring started at 300 rpm. Aninitiator solution was made by dissolving 1.0 g of ammonium persulfatein 2.0 g of distilled water. The solution was filtered and approximately550 μL were added to the prepolymer solution. After mixing, the solutionwas added to the reaction vessel. After 5 to 10 min, a solution of 0.35mL of SPAN®80 in 10 mL of mineral oil was added and the resultingsuspension was allowed to polymerize for at least 4 hr.

Example 10 Particle Prepared with a Peptide Crosslinker

A prepolymer solution was prepared by dissolving 3.8 g of acrylamide,5.4 g of 3-sulfopropyl acrylate potassium salt, and 0.05 g of apeptide-based crosslinker, prepared as in Example 2, in 10.0 g ofdistilled water. This solution was filtered and then vacuum degassed for5 min and flushed with argon. Mineral oil (300 mL) was sonicated for 1hr and then added to a sealed reaction vessel equipped with an overheadstirring element. The vessel was vacuum degassed for 1 hr and then thevacuum replaced with argon. N,N,N′,N′-tetramethylethylenediamine (2 mL)was added to the reaction vessel and overhead stirring started at 300rpm. An initiator solution was made by dissolving 1.0 g of ammoniumpersulfate in 2.0 g of distilled water. The solution was filtered and300 μL were added to the prepolymer solution. After mixing, the solutionwas added to the reaction vessel. After 5 to 10 min, a solution of 0.5mL of SPAN®80 in 10 mL of mineral oil was added and the resultingsuspension was allowed to polymerize for 5 hr.

Example 11 Purification of Particles

After the polymerization was complete, the mineral oil was decanted fromthe reaction vessel and the polymer particles were washed four timeswith fresh portions of hexane to remove the mineral oil. The particleswere then transferred to a separatory funnel with phosphate bufferedsaline (PBS) and separated from residual mineral oil and hexane. Theresulting mixture was washed twice with PBS.

The particles were separated into sizes using sieving. Sieves werestacked from the largest size (on top) to the smallest size (on bottom).A sieve shaker was utilized to aid the sieving process. The particleswere placed on the top sieve along with PBS. Once all the particles hadbeen sorted, they were collected and placed in bottles according totheir sizes.

After sieving, the particles were dehydrated to extend their shelf life.Under stirring, the particles were placed in a graded series ofsolvent/water mixtures. Both acetone and ethanol were used successfullyto dehydrate the particles. For at least 4 hrs, the particles weresuspended in 75% solvent, 85% solvent, 95% solvent, 97% solvent, and100% solvent. Subsequently, the particles were lyophilized, packaged,and sterilized.

Example 12 Determination of Delivery Characteristics of the Particles

To evaluate the delivery characteristics, particles prepared in asimilar manner to Example 9 were injected through a Headway 17microcatheter (0.017″, 432 μm inner lumen) with a figure-eight knot of4.5×1.5 cm. The test sample was prepared by mixing 2 to 3 mL ofparticles, 3 to 4 mL of saline, and 4 to 5 mL of contrast. The sampleswere injected through the microcatheter and into a dish using a 1 mLsyringe. Pictures were taken of the particles before and after injectionthrough the microcatheter. The diameter and the circularity of theparticles was determined using Axiovision image analysis software. Thetable below summarizes the results.

In some embodiments, the form factor of a region describes the form of aregion on the basis of its circularity. A perfect circle is given thevalue 1. The more elongated the region is, the smaller the form factor.The calculation is based on the Area filled and Perimeter Croftonparameters.

Pre-Injection Post-injection 0.25% Circularity 0.94 ± 0.05 0.97 ± 0.02Crosslinker Diameter 0.38 ± 0.09 mm 0.48 ± 0.11 mm 0.5% Circularity 0.99± 0.01 0.96 ± 0.08 Crosslinker Diameter 0.43 ± 0.13 mm 0.47 ± 0.09 mm0.75% Circularity 0.93 ± 0.11 0.98 ± 0.01 Crosslinker Diameter 0.49 ±0.10 mm 0.45 ± 0.08 mm

No change in the circularity or diameter of the particles was observed,indicating that the particles did not break apart or fragment duringdelivery through a micro catheter. In other words, the particlesremained substantially intact when delivered through a catheter.

Example 13 Determination of In Vitro Hydrolytic Degradability

Samples of particles prepared with differing amounts of crosslinker wereplaced in PBS and stored at 37° C. to determine degradation time. Thevisual analysis included color and transparency of the particles,ability to see the particle outline, and the number of particlesvisible. The grading scale for the samples included (5) no change inparticle numbers, outlines, or quantity from the beginning of theexperiment, (3) faint particle outline with a good number of particlesstill visible, (1) very few particles visible, and (0) no particlesobserved in sample. Results are illustrated in FIG. 1. The resultsillustrate that degradation can be dependent on the crosslinkerconcentration. For example, the longest degradation time occurred withthe largest crosslinker concentration.

FIG. 2 graphically illustrates degradation time at 37° C. as a functionof the amount of crosslinker. As illustrated, the greater the percentageof crosslinker, the longer degradation takes. Additionally, the largerthe particle diameter (numbers on right of graph in micrometers), thelonger the degradation. As such, the particles with the longestdegradation time are those that have the largest concentration ofcrosslinker and the largest diameter. These two properties can be variedto tailor degradation time as needed.

Example 14 Tetra Ester Crosslinker

To a 200 mL pear-shaped flask, 10 g (84.8 mmol) of succinic acid, 40 g(0.689 mol) of allyl alcohol and 30 μL of 98% H₂SO₄ were added. Thereaction mixture was refluxed for 6 hrs and then quenched by theaddition of 25 mL of 1 M sodium carbonate solution. The solvent wasremoved under vacuum. The crude was reconstituted in 25 mL of water andthe product, diallyl succinate, was extracted with ethyl acetate, 4×50mL. The organic phase was collected and dried with MgSO₄ and the solventwas then removed in vacuo to give 9.26 g of diallyl succinate.

To a 1 L round bottom flask, 5.2 g (26.3 mmol) of diallyl succinate and20 g (0.116 mol) of meta-chloroperoxybenzoic acid (mCPBA) were dissolvedin 400 mL of dichloromethane. The reaction mixture was refluxed at 40°C. overnight. The reaction mixture was then passed through an Amberlystfree base column to remove the by-product, m-chlorobenzoic acid. Thesolvent was removed under vacuum to give the crude. Chromatography usingethyl acetate in hexane from 5% to 20% at 210 nm gave the purediglycidyl succinate.

To a 20 mL vial, 1.15 g (5 mmol) of diglycidyl succinate, 950 mg (11mmol) of methacrylic acid and 1.5 g (7 mmol) of1-butyl-3-methylimidazolium bromide ([bmim]Br) were added. The reactionmixture was stirred at 75° C. After 1 hr, the TLC showed no presence ofthe epoxide. The reaction mixture was suspended in 50 mL of 1 M sodiumcarbonate solution and the product was extracted with ethyl acetate,3×50 mL. The organic layer was collected and dried over MgSO₄, and thenconcentrated under vacuum. The TLC ran with 50:50 ethylacetate:dichloromethane showed only one spot. Two grams of the titletetra ester crosslinker was collected with 99% yield.

Example 15 Tetra Thioester Crosslinker

To a 500 mL 3-neck round bottom flask under argon chilled at 0° C., 100mL of dry THF was added. Under stirring, 20 g (0.11 mol) of2,2′-(ethylenedioxy)ethanthiol and 16 mL (0.09 mol) ofdiisopropylethylamine were added. To 40 mL of dry THF, 5 mL (0.045 mol)of succinyl chloride was dissolved. Under argon, the solution was addeddrop wise into the reaction mixture at 0° C. via an addition funnel withvigorous stirring. Following the addition, the reaction mixture wasstirred for 1 hr at 0° C. and then allowed to warm up to roomtemperature to stir overnight. The reaction mixture was then chilled onice to precipitate the amine salt. The white precipitate was removed byfiltering through a medium fritted glass filter and washed with ice coldTHF. The filtrate was collected and concentrated under vacuum. Flashchromatography with ethyl acetate in DCM from 0% to 15% at 254 nm gavethe dithiol ester intermediate.

To a 250 mL 3-neck round bottom flask under argon chilled at 0° C., 50mL of dry THF was added. Under stirring, 3.17 g (7.1 mmol) of dithiolester intermediate and 3.6 mL (20 mmol) of diisopropylethylamine wereadded. To 50 mL of dry THF, 2 mL (20 mmol) of methacryloyl chloride wasdissolved. Under argon, the solution was added drop wise into thereaction mixture at 0° C. via an addition funnel with vigorous stirring.Following the addition, the reaction mixture was stirred for 1 hr at 0°C. and then allowed to warm up to room temperature to stir overnight.The reaction mixture was then chilled on ice to precipitate the aminesalt. The white precipitate was removed by filtering through a mediumfritted glass filter and washed with ice cold THF. The filtrate wascollected and concentrated under vacuum. Flash chromatography with ethylacetate in dichloromethane from 0% to 10% at 254 nm eluted the desiredtetra thiol ester crosslinker from 4 min to 12 min. The massspectrometry analysis gave 605.1 corresponding to [M+Na]⁺ of thecalculated mass of C₂₄H₃₈O₈S₄.

Example 16 Particle Prepared with a Peptide Crosslinker

A prepolymer solution was prepared by dissolving 3.1 g of acrylamide,7.3 g of 3-sulfopropyl acrylate potassium salt, and 0.2 g of apeptide-based crosslinker, prepared as in Example 3, in 10.0 g ofdistilled water. This solution was filtered and then vacuum degassed for5 min and flushed with argon. Mineral oil (500 mL) was sonicated for 1hr and then added to a sealed reaction vessel equipped with an overheadstirring element. The vessel was vacuum degassed for at least 1 hr andthen the vacuum replaced with argon.N,N,N′,N′-tetramethylethylenediamine, approximately 2 mL, was added tothe reaction vessel and overhead stirring started at 300 rpm. Aninitiator solution was made by dissolving 1.0 g of ammonium persulfatein 2.0 g of distilled water. The solution was filtered and approximately250 μL added to the prepolymer solution. After mixing, the solution wasadded to the reaction vessel. Subsequently, a solution of 0.35 mL ofSPAN®80 in 10 mL of mineral oil was added and the resulting suspensionwas allowed to polymerize for at least 4 hr.

Example 17 Determination of In Vitro Enzymatic Degradability

Samples of particles prepared with a peptide crosslinker were placed inPBS, with and without an enzyme, and incubated at 37° C. or 55° C. todetermine degradation time. Samples included a high enzyme concentrationand a low enzyme concentration.

The visual analysis included color and transparency of the particles,ability to see the particle outline, and the number of particlesvisible. The grading scale for the samples included (5) no change inparticle numbers, outlines, or quantity from the beginning of theexperiment, (3) faint particle outline with a good number of particlesstill visible, (1) very few particles visible, and (0) no particlesobserved in sample. Results are illustrated in FIG. 3. The resultsillustrate that the particles are slow to hydrolytically degrade, butthe rate of degradation can be increased in the presence of an adequateenzyme. For example, the shortest degradation time occurred with thehighest concentration of enzyme present in the PBS solution.

The preceding disclosures are illustrative embodiments. It should beappreciated by those of skill in the art that the devices, techniquesand methods disclosed herein elucidate representative embodiments thatfunction well in the practice of the present disclosure. However, thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsthat are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the invention.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on those preferred embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects those of ordinary skill in the art toemploy such variations as appropriate, and the inventors intend for theinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

Further, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. An embolic system including: a delivery device; and anembolic solution including polymer particles, wherein the polymerparticles include: an acrylate, acrylamide, methacrylamide, methylmethacrylate, or a combination thereof, and a crosslinker, wherein thepolymer particles have a spherical diameter between about 40 μm andabout 1,200 μm.
 2. The embolic system of claim 1, wherein the polymerparticles are susceptible to degradation through hydrolysis or enzymaticaction, and wherein the degradation provides less than about 10% of thepolymer particles intact after about 5 days.
 3. The embolic system ofclaim 1, wherein the spherical diameter is between about 75 μm and about1,200 μm.
 4. The embolic system of claim 1, wherein the crosslinkerincludes at least two functional groups.
 5. The embolic system of claim1, wherein the crosslinker includes at least one linkage susceptible todegradation through hydrolysis or enzymatic action.
 6. The embolicsystem of claim 1, wherein the crosslinker is bis-glycidyl aminoalcohol,

wherein a, b, c, d, e, and f are each independently 1-20.
 7. The embolicsystem of claim 5, wherein the at least one linkage is an ester, athioester, a carbonate, a peptide cleavable by matrixmetalloproteinases, a peptide cleavable by matrix collagenases, apeptide cleavable by matrix elastases, a peptide cleavable by matrixcathepsins, or a combination thereof.
 8. The embolic system of claim 1,including a second crosslinker including a second linkage selected froman ester, a thioester, a carbonate, a peptide cleavable by matrixmetalloproteinases, a peptide cleavable by matrix collagenases, apeptide cleavable by matrix elastases, and a peptide cleavable by matrixcathepsins.
 9. The embolic system of claim 1, wherein the crosslinker isbis-glycidyl amino alcohol or bi-functionalizedmethacryloyl-Ala-Pro-Gly-Leu-AEE-methacrylate.
 10. The embolic system ofclaim 1, wherein the delivery device is a catheter.
 11. The embolicsystem of claim 1, wherein the delivery device is a microcatheter. 12.The embolic system of claim 1, wherein the delivery device is a needle.13. The embolic system of claim 1, wherein the delivery device and theembolic solution are sterilized.
 14. The embolic system of claim 1,wherein the embolic solution includes a monomer including an ionizablefunctional group.
 15. The embolic system of claim 14, wherein theionizable functional group is basic or acidic.
 16. The embolic system ofclaim 1, wherein the embolic solution includes a radiopaque contrastagent.
 17. The embolic system of claim 1, wherein the embolic solutionincludes a dye.
 18. The embolic system of claim 1, wherein the embolicsolution is provided in a vial.
 19. The embolic system of claim 1,wherein the embolic solution is provided in a syringe.
 20. The embolicsystem of claim 1, wherein the polymer particles have a circularitygreater than about 0.9.